title: Cell-specific actions of a human LHX3 gene enhancer during pituitary and spinal cord development.
abstract: The LIM class of homeodomain protein 3 (LHX3) transcription factor is essential for pituitary gland and nervous system development in mammals. In humans, mutations in the LHX3 gene underlie complex pediatric syndromes featuring deficits in anterior pituitary hormones and defects in the nervous system. The mechanisms that control temporal and spatial expression of the LHX3 gene are poorly understood. The proximal promoters of the human LHX3 gene are insufficient to guide expression in vivo and downstream elements including a conserved enhancer region appear to play a role in tissue-specific expression in the pituitary and nervous system. Here we characterized the activity of this downstream enhancer region in regulating gene expression at the cellular level during development. Human LHX3 enhancer-driven Cre reporter transgenic mice were generated to facilitate studies of enhancer actions. The downstream LHX3 enhancer primarily guides gene transcription in α-glycoprotein subunit -expressing cells secreting the TSHβ, LHβ, or FSHβ hormones and expressing the GATA2 and steroidogenic factor 1 transcription factors. In the developing nervous system, the enhancer serves as a targeting module active in V2a interneurons. These results demonstrate that the downstream LHX3 enhancer is important in specific endocrine and neural cell types but also indicate that additional regulatory elements are likely involved in LHX3 gene expression. Furthermore, these studies revealed significant gonadotrope cell heterogeneity during pituitary development, providing insights into the cellular physiology of this key reproductive regulatory cell. The human LHX3 enhancer-driven Cre reporter transgenic mice also provide a valuable tool for further developmental studies of cell determination and differentiation in the pituitary and nervous system.
authors.affiliation: PhD, Department of Biology, Indiana University-Purdue University Indianapolis, LD222, 402 North Blackford Street, Indianapolis, IN 46202-5120. srhodes@iupui.edu.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Park
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Mullen
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Rhodes
mesh_terms: D000818:Animals; D019070:Cell Lineage; D003433:Crosses, Genetic; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005260:Female; D050989:GATA2 Transcription Factor / Q000378:metabolism; D005838:Genotype; D015292:Glycoprotein Hormones, alpha Subunit / Q000378:metabolism; D052681:Gonadotrophs / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism; D006801:Humans; D019426:Integrases / Q000378:metabolism; D007395:Interneurons / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D037101:Luteinizing Hormone, beta Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes
chemical_list: D050989:GATA2 Transcription Factor; D015292:Glycoprotein Hormones, alpha Subunit; D060850:LIM-Homeodomain Proteins; C094898:Lhx3 protein; D037101:Luteinizing Hormone, beta Subunit; D014157:Transcription Factors; D013006:Growth Hormone; C045073:Cre recombinase; D019426:Integrases